Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a ... Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a characteristic facial appearance. Defective bone remodeling of the skull results in choanal stenosis with concomitant respiratory problems and feeding difficulties, which are the first clinical manifestation of disease. The expanding bone encroaches on neural foramina, leading to blindness, deafness, and facial palsy. Complete visual loss invariably occurs in all untreated patients, and hearing loss is estimated to affect 78% of patients with OPT. Tooth eruption defects and severe dental caries are common. Calcium feedback hemostasis is impaired, and children with OPT are at risk of developing hypocalcemia with attendant tetanic seizures and secondary hyperparathyroidism. The most severe complication of OPT, limiting survival, is bone marrow insufficiency. The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the liver and spleen (summary by Aker et al., 2012). - Genetic Heterogeneity of Autosomal Recessive Osteopetrosis Other forms of autosomal recessive infantile malignant osteopetrosis include OPTB4 (611490), which is caused by mutation in the CLCN7 gene (602727) on chromosome 16p13, and OPTB5 (259720), which is caused by mutation in the OSTM1 gene (607649) on chromosome 6q21. A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2; 259710) is caused by mutation in the TNFSF11 gene (602642) on chromosome 13q14, an intermediate form (OPTB6; 611497) is caused by mutation in the PLEKHM1 gene (611466) on chromosome 17q21, and a severe osteoclast-poor form associated with hypogammaglobulinemia (OPTB7; 612301) is caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q22.1. Another form of autosomal recessive osteopetrosis (OPTB8; 615085) is caused by mutation in the SNX10 gene (614780) on chromosome 7p15. A form of autosomal recessive osteopetrosis associated with renal tubular acidosis (OPTB3; 259730) is caused by mutation in the gene encoding carbonic anhydrase II (611492) on chromosome 8q22. Autosomal dominant forms of osteopetrosis are more benign (see OPTA1, 607634). Osteosclerosis also occurs in pycnodysostosis (265800), in van Buchem disease (239100), and in sclerosteosis (269500).
Patients with osteopetrosis display macrocephaly, progressive deafness and blindness, hepatosplenomegaly, and severe anemia beginning in early infancy or in fetal life. Deafness and blindness are generally thought to represent effects of pressure on nerves. (Keith (1968) presented evidence ... Patients with osteopetrosis display macrocephaly, progressive deafness and blindness, hepatosplenomegaly, and severe anemia beginning in early infancy or in fetal life. Deafness and blindness are generally thought to represent effects of pressure on nerves. (Keith (1968) presented evidence he interpreted as indicating that primary retinal atrophy, not optic atrophy from nerve pressure, occurs in osteopetrosis.) The anemia is caused by encroachment of bone on marrow, resulting in obliteration, and the hepatosplenomegaly is caused by compensatory extramedullary hematopoiesis. The condition results from defective resorption of immature bone. Prenatal diagnosis is possible by x-ray. Enell and Pehrson (1958) described 2 sibs and a cousin affected with the early severe form in a highly inbred kindred. In 2 Palestinian Muslim families that lived in the same village, Dudin and Rambaud-Cousson (1993) found 7 cases of lethal infantile osteopetrosis. In 2 of the 7 persons, short-segment Hirschsprung disease (142623), a probably independent disorder, was also present. Orchard et al. (1992) found that the serum of 13 patients with what they termed malignant osteopetrosis showed radioimmunoassay levels of CSF1 equal to or higher than control serum. In addition, serum from 6 osteopetrotic patients was tested in a bioassay to determine if the CSF1 present was biologically active; in all cases there was demonstrable activity in these samples.
Frattini et al. (2000) showed that TCIRG1 (604592), encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, was mutated in 5 of 9 patients with infantile malignant osteopetrosis (see, e.g., 604592.0001-604592.0003). Kornak et al. (2000) reported 5 ... Frattini et al. (2000) showed that TCIRG1 (604592), encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, was mutated in 5 of 9 patients with infantile malignant osteopetrosis (see, e.g., 604592.0001-604592.0003). Kornak et al. (2000) reported 5 patients in whom different mutations were identified in at least 1 TCIRG1 allele (see, e.g., 604592.0004-604592.0005). An additional patient from a consanguineous family was not homozygous for markers flanking the locus, suggesting that a second locus may exist for infantile malignant osteopetrosis. Janssens and Van Hul (2002) reviewed the process of bone remodeling and the genetic defects resulting in aberrant bone formation and resorption. In a child from a consanguineous Turkish kindred who manifested osteopetrosis and distal RTA (see OPTB3, 259730), Borthwick et al. (2003) excluded defects in the CA2 gene and found instead penetrance of 2 separate recessive disorders, each affecting a different, tissue-specific subunit of the vacuolar proton pump H(+)-ATPase. The osteopetrosis was the result of a homozygous deletion in TCIRG1 (604592.0007), whereas the distal RTA was associated with a homozygous mutation in the ATP6V1B1 gene (192132.0005), which encodes the kidney-specific B1 subunit of H(+)-ATPase. Borthwick et al. (2003) concluded that coinheritance of 2 rare recessive disorders created a phenocopy of CA2 deficiency in this patient.
By a systematic search for osteopetrosis in the county of Funen, Denmark, the prevalence of this category of bone disorder was found to be 5.5 per 100,000 persons (Bollerslev, 1987). Of the 33 patients, 32 had the mild, ... By a systematic search for osteopetrosis in the county of Funen, Denmark, the prevalence of this category of bone disorder was found to be 5.5 per 100,000 persons (Bollerslev, 1987). Of the 33 patients, 32 had the mild, autosomal dominant form. Thirty-nine percent were asymptomatic. Two obligate carriers, who had the genotype but were not phenotypically affected, were found. The frequency of fractures was low. An unusually high frequency of recessive osteopetrosis has been observed in Costa Rica (Loria-Cortes et al., 1977).